Biology:Tripeptidyl peptidase I

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.

Structure

Gene

The human gene TPP1 encodes a member of the sedolisin family of serine proteases. The human gene has 13 exons and locates at the chromosome band 11p15.

Protein

The human TPP1 is 61kDa in size and composed of 563 amino acids. An isoform of 34.5kDa and 320 amino acids is generated by alternative splicing and a peptide fragment of 1-243 amino acid is missing. TPP1 contains a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad. It also contains an octahedrally coordinated Ca²⁺-binding site that are characteristic features of the S53 sedolisin family of peptidases. Unlike other S53 peptidases, it has steric constraints on the P4 substrate pocket, which might contribute to its preferential cleavage of tripeptides from the unsubstituted N-terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1.

Function

High expression of TPP1 is found in bone marrow, placenta, lung, pineal and lymphocytes. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates and has weaker endopeptidase activity. It is synthesized as a catalytically inactive enzyme which is activated and autoproteolyzed upon acidification.

Clinical significance

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders with pathological phenotypes that auto fluorescent lipopigments present in neurons and other cell types. Over the past two decades, accumulating evidences indicates that NCLs are caused by mutations in eight different genes, including genes encoding several soluble proteins (cathepsin D, PPT1, and TPP1). Mutations of gene TPP1 result in late-infantile neuronal ceroid lipofuscinosis which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. Mutations in the TPP1 gene lead to late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood. It has been demonstrated that a single injection of intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct at an early stage in the disease progression could substantially inhibit the development of disease-related retinal function deficits and structural changes. This result implies that ex vivo gene therapy using autologous stem cells may be an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.

Further reading

• "Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5". Human Mutation 14 (3): 199–215. 1999. doi:10.1002/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A. PMID 10477428. 
• "Batten's disease: clues to neuronal protein catabolism in lysosomes". Journal of Neuroscience Research 60 (2): 133–40. April 2000. doi:10.1002/(SICI)1097-4547(20000415)60:2<133::AID-JNR1>3.0.CO;2-3. PMID 10740217. 
• "Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2)". Current Molecular Medicine 2 (5): 423–37. August 2002. doi:10.2174/1566524023362294. PMID 12125808. 
• "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. January 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• "Purification and characterization of a tripeptidyl peptidase I from human osteoclastomas: evidence for its role in bone resorption". Archives of Biochemistry and Biophysics 306 (2): 354–9. November 1993. doi:10.1006/abbi.1993.1523. PMID 8215436. 
• "Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis". Science 277 (5333): 1802–5. September 1997. doi:10.1126/science.277.5333.1802. PMID 9295267. 
• "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• "Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1429 (2): 496–500. January 1999. doi:10.1016/S0167-4838(98)00238-6. PMID 9989235. 
• "Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I". FEBS Letters 443 (2): 131–5. January 1999. doi:10.1016/S0014-5793(98)01683-4. PMID 9989590. 
• "Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder". American Journal of Human Genetics 64 (6): 1511–23. June 1999. doi:10.1086/302427. PMID 10330339. 
• "Purification and characterization of bovine brain lysosomal pepstatin-insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscinosis". Journal of Neurochemistry 74 (1): 287–94. January 2000. doi:10.1046/j.1471-4159.2000.0740287.x. PMID 10617131. 
• "Characterization of endopeptidase activity of tripeptidyl peptidase-I/CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis". Biochemical and Biophysical Research Communications 268 (3): 904–8. February 2000. doi:10.1006/bbrc.2000.2207. PMID 10679303. 
• "Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis". Neurogenetics 1 (3): 217–22. March 1998. doi:10.1007/s100480050032. PMID 10737126. 
• "Tripeptidyl peptidase I, the late infantile neuronal ceroid lipofuscinosis gene product, initiates the lysosomal degradation of subunit c of ATP synthase". Journal of Biochemistry 128 (3): 509–16. September 2000. doi:10.1093/oxfordjournals.jbchem.a022781. PMID 10965052. 
• "The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH". The Journal of Biological Chemistry 276 (3): 2249–55. January 2001. doi:10.1074/jbc.M008562200. PMID 11054422. 
• "Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis". American Journal of Medical Genetics 99 (2): 161–3. March 2001. doi:10.1002/1096-8628(2001)9999:9999<::AID-AJMG1145>3.0.CO;2-Z. PMID 11241479. 
• "Heterogeneity of late-infantile neuronal ceroid lipofuscinosis". Genetics in Medicine 2 (6): 312–8. 2001. doi:10.1097/00125817-200011000-00002. PMID 11339651. 

External links

• The MEROPS online database for peptidases and their inhibitors: S53.003
• GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinoses
• Overview of all the structural information available in the PDB for UniProt: O14773 (Tripeptidyl-peptidase 1) at the PDBe-KB.